Stress-induced alterations in amygdala-LC interactions

压力引起的杏仁核-LC 相互作用的改变

• 批准号: 7050173
• 负责人: ANTHONY A GRACE
• 金额: $ 32.06万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050173
• 关键词: amygdala; behavior test; cold temperature; corticotropin releasing factor; drug abuse; electrophysiology; excitatory aminoacid; histology; laboratory rat; locus coeruleus; mental disorders; neuropsychology; norepinephrine; relapse /recurrence; startle reaction; stress

DESCRIPTION (provided by applicant): Stress is known to be a factor in the etiology or exacerbation of psychiatric disorders, and plays an important role in reinstatement of drug-taking behavior. This proposal will use primarily electrophysiological recordings in anesthetized rats to examine the effects of acute and chronic stress on the regulation of the locus coeruleus (LC) by the amygdalar complex. Norepinephrine and corticotropin releasing hormone have been identified as central factors in the response to stress. In particular, the noradrenergic neurons of the LC are known to have a major role in central mediation of stress responses. These neurons are driven by a number of afferent influences. One set of afferents that appears to have a primary role in stress as it relates to psychiatric disorders and relapse to drug abuse are the projections that involve the amygdala. We propose to examine amygdalar regulation of LC neuron activity, and how this system is modified by acute and chronic stress. Our central hypothesis is that chronic stress causes a sensitization of LC neuron responsivity via its effects on amygdalofugal pathways. This will be done along four specific aims: 1) to examine the physiology of projection systems connecting the basolateral amygdala complex with the LC, 2) to examine the response of this system to acute stressors (footshock), and how these responses are modified following chronic cold exposure, 3) to evaluate the nature of the change in LC neuron responsivity following chronic stress, and 4) to determine whether the alteration in LC responsivity following chronic stress can be altered by selective interruption of these amygdalar efferents. We will use primarily in vivo single unit and intracellular recording methods to examine systems-level interactions, with in vitro recordings used to measure persistent changes in LC neuronal activity and to address specific pathway-related questions as they arise. We will independently verify the behavioral effects of chronic cold exposure by measuring acoustic startle, a response that is sensitive to manipulations of the central amygdala and forebrain NE systems. We hope that a better understanding of amygdalar-coerulear systems will lead to insights into how stress-induced pathophysiology in these pathways can, in part, mediate some of the behavioral symptoms of psychiatric disease and drug-abuse disorders.

描述（由申请人提供）：众所周知，压力是精神疾病的病因或恶化的一个因素，并且在恢复吸毒行为方面发挥着重要作用。该提案将主要使用麻醉大鼠的电生理记录来检查急性和慢性应激对杏仁核复合体对蓝斑（LC）调节的影响。去甲肾上腺素和促肾上腺皮质激素释放激素已被确定为应激反应的核心因素。特别是，已知 LC 的去甲肾上腺素能神经元在应激反应的中枢调节中具有重要作用。这些神经元由许多传入影响驱动。一组传入神经似乎在压力中起主要作用，因为它与精神疾病和药物滥用复发有关，这些传入神经是涉及杏仁核的投射。我们建议检查杏仁核对 LC 神经元活动的调节，以及该系统如何被急性和慢性应激改变。我们的中心假设是，慢性压力通过影响杏仁核通路，导致 LC 神经元反应性敏感。这将按照四个具体目标来完成：1）检查连接基底外侧杏仁核复合体与 LC 的投射系统的生理学，2）检查该系统对急性应激源（足部电击）的反应，以及如何根据以下情况修改这些反应慢性寒冷暴露，3) 评估慢性应激后 LC 神经元反应性变化的性质，4) 确定慢性应激后 LC 反应性的变化是否可以通过选择性中断来改变这些杏仁核传出神经。我们将主要使用体内单个单元和细胞内记录方法来检查系统级相互作用，并使用体外记录来测量 LC 神经元活动的持续变化，并解决出现的特定通路相关问题。我们将通过测量声惊吓来独立验证慢性寒冷暴露的行为影响，这是一种对中央杏仁核和前脑 NE 系统的操作敏感的反应。我们希望更好地了解杏仁核-蓝核系统将有助于深入了解这些途径中压力诱导的病理生理学如何在一定程度上介导精神疾病和药物滥用障碍的一些行为症状。